PRA International is a leading contract research organization with a primary focus on clinical development on an international scale. Our central registered pharmacy, PRA International – RX, provides clinical supplies labeling and distribution services for many of the clinical trials managed by PRA.
This letter provides comments on the draft Guidance for Industry, “Handling and retention of BA and BE Testing Samples” issued in August 2002 (Docket No. 02D-0350). With this guidance document, the Agency seeks to define acceptable procedures for selecting reserve samples of investigational product utilized in BA and BE studies, as required by 21 CFR 320.38 and § 320.63. The important issues here are that reserve samples of investigational product be truly representative of the materials administered, and that the samples be readily available to FDA’s Division of Scientific Investigations and field inspectors from the Office of Regulatory Affairs. In the draft guidance, testing facilities alone may select the reserve samples of investigational product.
Although PRA strongly supports the intent of the guidance, we feel that selection and retention of the reserve samples would be most effective if performed by qualified independent contractors such as a third party contracted to perform clinical supplies management, often part of a Contract Research Organization (CRO). PRA believes that sample selection would be equally objective by a CRO or testing facility as both entities are independent contractors of the sponsor.
1. Drawbacks of requiring that testing facilities select reserve samples
Having the testing facility (clinical site) select the samples has several drawbacks, as follows:
· For blinded studies, site personnel are blinded to the treatment. Thus, random selection of samples may result in an insufficient quantity of study drug from one or more of the treatment arms.
· EACH testing facility would be required to reserve sufficient quantity to perform five times all of the release tests required in the application. For multi-site studies, this could be a significant burden on sponsor and sites, without any perceived benefit in ensuring the quality of the data.
2. Suggested changes to the draft guidance
PRA would suggest that the guidance allow CROs that do not manufacture the drug product to perform the function of randomly selecting samples (from each different shipment of supplies from the sponsor/manufacturer) and of storing these samples as required by 21 CFR 320.38 and § 320.63. Using the example of a blinded study, the following outlines our proposal of how sample selection could be carried out by an CRO:
· The sponsor or drug manufacturer would ship the blinded product to an CRO – labeled or unlabeled.
· The CRO would label the drug product (if needed). If the CRO received the drug product already labeled for subjects, the CRO would be provided with the randomization lists.
· Using the randomization code lists, the CRO would randomly select samples from the labeled drug product – in random “blocks” that would not disrupt the randomization scheme.
· The CRO would then store the samples for the time required under §§ CFR 320.38 and 320.63.
PRA also suggests that the CRO be required to keep records of the chain of custody of the study drug product to clearly show that the samples were randomly selected and that no entity had tampered with the samples originally selected.
A similar procedure could be used for open-label studies whereby the CRO would select the samples prior to sending drug product to sites, the critical issue being a meticulous record of the chain of custody and procedures followed in sample selection.
3. Advantages of the suggested changes
· The revisions suggested by PRA for blinded studies would ensure that a sufficient number of samples from each study treatment arm are reserved, and, as importantly, would ensure that the randomization scheme is maintained and that treatment arms are balanced over the entire study.
· The revisions would also allow for the manufacture of a decreased quantity of study drug supplies since samples would be collected at the CRO level rather than at the individual site level.
· The samples, if selected and stored by a CRO, would be properly maintained and readily available to FDA field inspectors at one location.
In summary, it should be noted that a contract between a Sponsor and a CRO and the subsequent transfer of responsibilities does not mean that the CRO cannot maintain its integrity if challenged by the Sponsor to perform an illegal or questionable act. There is no reason to expect a difference in this regard between testing facilities and CROs. Lastly, CROs are set up to perform the functions required by this guidance; the majority of testing facilities (sites) are not.